This project aims to test whether differences between HIV-1 subtypes B and C are responsible for differential incidence of HIV-associated dementia (HAD) between US & Indian populations, where HAD occurs reportedly at rates of 15-30% or 0.5% respectively. We previously showed that this differential incidence correlates with a specific defect in the chemokine motif of the subtype C HIV Tat protein. While subtype B Tat contains a dicysteine motif and displays monocyte chemotactic function, the subtype C Tat lacks both. Specific aims of this project are: (1) To examine the differential ability of subtype B and C HIV-1 to induce HIV-1 encephalitis in SCID mice in collaboration with Dr. William Tyor (Medical University of South Carolina), Dr. U. Ranga (JNCASR, Bangalore, India) and Dr. Hoby Hetherington (AECOM). In this mouse model, intracranial injection of HIV-1 infected human monocytes induces a spectrum of neuropathological and cognitive changes that mimic HAD. We will attempt to: (i) test if subtype C HIV is unable to induce HAD/HIVE and (ii) confirm a role for Tat and set the stage to identify other viral genes that play a role in HAD. Dr. Ranga will generate molecular clones of subtype C HIV from the same population where the low incidence of HAD was reported. In collaboration with Drs. Tyor and Hetherington, we will test the ability of the two subtypes of HIV to induce HIVE/HAD symptoms in mice. Following intracranial injection of HIV-infected human MDM, we will: (i) assess cognitive function using a Morris water maze; (ii) evaluate the extent and severity of neuronal injury using MR spectroscopic imaging; (iii) evaluate neuronal apoptosis and gliosis (migration of activated murine monocytes/microglia to the site of injection). We will correlate results from imaging, pathology and cognitive studies. In Aim 2, we will examine the hypothesis that absence of a functional chemokine motif in Tat protein is responsible for the low incidence of HAD in subtype C HIV-infected individuals by comparing the ability of human MDM expressing clade B or clade C Tat proteins to induce HAD in SCID HIVE model, such as cognitive defect, neuronal loss or gliosis. The neuronal loss will be determined by both MR imaging, while neuronal apoptosis and gliosis will be evaluated by histopathology using the Einstein Pathology core. The implications of this work to human health lie in the possibility that viral determinants of HAD can be identified hopefully leading to studies aimed at direct interventions for HAD.